PROJECT SUMMARY/ABSTRACT Glaucoma is an increasingly prevalent, progressive eye disease that ultimately leads to blindness, due to the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve. Elevated intraocular pressure (IOP), determined by the balance between aqueous humor secretion and aqueous humor outflow, is considered an important risk factor for glaucoma. The exact molecular mechanisms that trigger increases in IOP, decreases in aqueous outflow, death of RGCs, and loss of vision are poorly understood. Only a few spontaneously-occurring murine models of glaucoma have been described. Our preliminary data show that mice deficient in the a1 subunit of soluble guanylate cyclase (sGCa1-/- mice) spontaneously develop high IOP and glaucoma, characterized by loss of RGC's. This finding suggests a central role for NO/cGMP signaling in the regulation of IOP and the development of glaucoma. Importantly, pilot data suggest this increase in IOP occurs while the iridocorneal angle is open. The goal of this project is to establish sGCa1-/- mice as a novel, spontaneous and clinically relevant model for high IOP and primary open angle glaucoma (POAG) and to identify NO-cGMP signaling as a potential therapeutic target for elevated IOP and POAG. Our central hypothesis is that high IOP in sGCa1-/- mice is triggered by a reduction in aqueous humor outflow and results in death of RGCs, optic nerve damage and glaucoma. This hypothesis will be tested in two specific aims: Aim 1Determine the phenotypic changes in the anterior segment of the eyes of sGCa1-/- mice. We will investigate the impact of sGCa1-deficiency on IOP and determine if changes in IOP are (i) age related, (ii) gender specific, and (iii) coincide with vascular hypertension. We furthermore plan to investigate whether a decrease in aqueous humor outflow underlies the increased IOP observed in sGCa1-/- mice and whether the increase in IOP occurs while the iridocorneal angle is open or closed. In addition we propose to carefully characterize ocular expression and activity of the various sGC isoforms. Aim 2Determine the phenotypic changes in the posterior segment of the eyes of sGCa1-/- mice. These studies will determine whether the changes in IOP and aqueous outflow coincide with degeneration of retinal ganglion cells and nerve fibers and damage to the optic nerve. We believe that establishing this novel murine model (sGCa1-/- mice) of elevated IOP and glaucoma may not only identify a well-characterized signaling pathway (NO/cGMP signaling) as an important regulatory mechanism controlling aqueous outflow and IOP but may also inform the clinical development of existing cGMP-elevating therapeutic compounds for the treatment of glaucoma, and may provide an important tool for investigators to test other strategies for disease prevention and treatment of high IOP and glaucoma.